ABSTRACT The placenta is characterized by intimate contact between the maternal blood and fetal chorionic villi. This organ is a target for rubella, cytomegalovirus, herpes simplex, HIV-1, hepatitis B and C viruses and parvovirus B19 infection, by either direct or contiguous infection of placental cell layers, virion passage through a breach or by cell-associated transport. Most recently, Zika virus (ZIKV), a mosquito-borne flavivirus of significant public health concern in the Americas, was found to transmit from an infected mother to the developing fetus in utero , resulting in adverse pregnancy outcomes characterized by fetal brain abnormalities and microcephaly. The greatest risk of serious fetal sequelae is associated with ZIKV infection early in pregnancy, suggesting enhanced tropism for placental cells during the first- and second-trimester. However the mechanism by which ZIKV establishes placental and fetal infection is poorly understood. We seek to fill this gap in knowledge and develop a deeper mechanistic understanding for how macrophages in the maternal-fetal compartment maintain immune homeostasis and restrict ZIKV transmission to the developing fetus. ZIKV antigen has been detected in chronic villi, specifically within placental macrophages or Hofbauer cells (HCs) and histiocytes from women who gave birth to infants with microcephaly or had active ZIKV infection during pregnancy. ZIKV RNA has also been isolated from placental tissue in humans and from pregnant mice infected with ZIKV. Several studies, including one recently published by our group, identified HCs as target cells of viral infection in vivo and in vitro. We showed that primary human HCs isolated from full-term placentae are permissive to productive infection by a contemporary strain of ZIKV, PRVABC59 (PR 2015). Upon ZIKV infection, HCs produced IFN-? and pro-inflammatory cytokines, however, we observed little to no cell death. Our findings were the first to identify a permissive cell type for ZIKV infection in the placenta, however, it is still unclear what role decidual or fetal monocyte-derived macrophages play during ZIKV infection and whether these placental cells dynamically change during pregnancy to program more potent antiviral responses to virus infection later in pregnancy. Based on our preliminary studies, our proposal will address the central hypothesis that macrophages in the maternal-fetal compartment (decidual, placental and fetal) in early gestation are more permissive for ZIKV infection and replication as compared to late-gestation macrophages, directly corresponding to reduced potency of cell autonomous antiviral immune signaling. Our proposal is divided into two specific aims that seek: 1) To define the dynamics of innate immune signaling in macrophages at the maternal-fetal interface during pregnancy; and 2) To determine how macrophages in the maternal-fetal compartment control ZIKV infection during pregnancy. These studies will provide new insights to ZIKV immunity in humans, elucidate mechanisms of innate immune control within the placenta and contribute to development of urgently needed effective antiviral therapeutics and vaccines.